A model to study vitamin B12 form, function and deficiency

WARRENM_Q23DTP

Vegan and vegetarian diets have gained significant traction over the past decade, with more people than ever before making the switch.

Whilst many people are choosing to go plant-based for environmental reasons, others are adopting these diets because of their health benefits. However, while plant-based diets may have many health benefits, they can also result in nutrient deficiencies if not carefully planned as plant-based diets simply do not contain certain nutrients, such as vitamin B12.

This brilliant-red coloured nutrient is unique among the vitamins for many reasons, including the fact that it is made exclusively by only certain bacteria and hence animals such as ourselves have to acquire it from our diets and deliver it to where it is required.

The trafficking and delivery of the B12 is comparatively poorly understood and this project aims to gain a better understanding of how the process is orchestrated by studying B12 uptake and transport in the model animal system C. elegans.

In this project we will use state-of-the-art imaging techniques to follow the movement of B12 from bacterial cells through to its trafficking and delivery within the worm.

The project will identify some of the key components of the transport system by using B12 molecules with chemical war heads to allow their identification.
Genetic approaches including RNA approaches will allow the role of other genes to be probed.

Finally, analogues forms of B12 will be investigated for their ability to act as antivitamins and to inhibit key biological processes.

The project will provide new insights into how B12 is trafficked in biological systems and the effects of B12 deficiency on biochemical activities.

References

Deery E, Lawrence AD, Warren MJ (2022) Biosynthesis of cobamides: Methods for the detection, analysis and production of cobamides and biosynthetic intermediates. In Methods and Enzymology: Coenzyme B12 Enzymes. Methods Enzymol. 2022; 668: 3-23. doi: 10.1016/bs.mie.2022.01.013. PMID: 35589198.

Kieninger C, Deery E, Lawrence A, Podewitz M, Wurst K, Nemoto-Smith E, Widner FJ, Baker JA, Jockusch S, Kreutz CR, Liedl KR, Gruber K, Warren MJ, Kräutler B (2019) The Hydrogenobyric Acid Structure Reveals the Corrin Ligand as an Entatic State Module Empowering B12-Cofactors for Catalysis. Angew Chem Int Ed Engl. 58(31):10756-10760. doi: 10.1002/anie.201904713.

Lawrence AD, Nemoto-Smith E, Deery E, Baker JA, Schroeder S, Brown DG, Tullett JMA, Howard MJ, Brown IR, Smith AG, Boshoff HI, Barry CE, Warren MJ (2018) Construction of fluorescent analogues to follow the uptake and distribution of cobalamin (vitamin B12) in bacteria, worms and plants. Cell Chemical Biology 25, 1–11. doi.org/10.1016/j.chembiol.2018.04.012.

Moore SJ., Sowa ST., Schuchardt C., Deery E., Lawrence AD., Ramos JV., Billig S., Birkemeyer C., Chivers PT., Howard MJ., Rigby SEJ., Layer G and Warren MJ (2017) Elucidation of the biosynthesis of the methane catalyst coenzyme F430. Nature 543(7643):78-82 DOI 10.1038/nature21427.

Bunbury F, Deery E, Sayer AP, Bhardwaj V, Harrison EL, Warren MJ, Smith AG (2022). Exploring the onset of B12 -based mutualisms using a recently evolved Chlamydomonas auxotroph and B12 -producing bacteria. Environ Microbiol. 2022 May 20. doi: 10.1111/1462-2920.16035. Online ahead of print. PMID: 35593514.